The long term goal of this research has been and remains to determine the factors and mechanisms involved in the regulation of hepatic glycogen synthesis and to determine how diabetes mellitus affects these regulatory processes. The study is being carried out using the isolated perfused rat liver which eliminates many of the factors complicating in vivo studies. The questions to be answered are: 1) How does insulin effect hepatic glycogenesis? 2) Is insulin involved in regulation of hepatic glycogenesis by glucose, and if so, how? 3) Do glucocorticoids directly activate hepatic glycogenesis, and if so, how? 4) What effect does diabetes have on regulation of hepatic glycogenesis by effector molecules? Glycogen synthesis will be examined by observing the actions of effector molecules and metabolic states on tissue metabolites and enzyme activities involved in glycogen metabolism in order to localize sites of action. Particular emphasis will be placed on the roles of cyclic AMP and cyclic GMP in the regulation of hepatic glycogenesis. A study of this nature should lead to a better understanding of the regulation of hepatic glycogen metabolism while at the same time increasing current knowledge of mechanisms of hormone action. BIBLIOGRAPHIC REFERENCE: Exton, J.H., Miller, T.B., Jr., Harper S.C., and Park, C.R., Effects of adrenalectomy and steroid replacement on gluconeogenesis and glycogen metabolism in perfused livers from fasted rats. American J. Physiol. (1975).